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1.
N Engl J Med ; 374(19): 1842-1852, 2016 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-27168434

RESUMO

BACKGROUND: Tracking longitudinal measurements of growth and decline in lung function in patients with persistent childhood asthma may reveal links between asthma and subsequent chronic airflow obstruction. METHODS: We classified children with asthma according to four characteristic patterns of lung-function growth and decline on the basis of graphs showing forced expiratory volume in 1 second (FEV1), representing spirometric measurements performed from childhood into adulthood. Risk factors associated with abnormal patterns were also examined. To define normal values, we used FEV1 values from participants in the National Health and Nutrition Examination Survey who did not have asthma. RESULTS: Of the 684 study participants, 170 (25%) had a normal pattern of lung-function growth without early decline, and 514 (75%) had abnormal patterns: 176 (26%) had reduced growth and an early decline, 160 (23%) had reduced growth only, and 178 (26%) had normal growth and an early decline. Lower baseline values for FEV1, smaller bronchodilator response, airway hyperresponsiveness at baseline, and male sex were associated with reduced growth (P<0.001 for all comparisons). At the last spirometric measurement (mean [±SD] age, 26.0±1.8 years), 73 participants (11%) met Global Initiative for Chronic Obstructive Lung Disease spirometric criteria for lung-function impairment that was consistent with chronic obstructive pulmonary disease (COPD); these participants were more likely to have a reduced pattern of growth than a normal pattern (18% vs. 3%, P<0.001). CONCLUSIONS: Childhood impairment of lung function and male sex were the most significant predictors of abnormal longitudinal patterns of lung-function growth and decline. Children with persistent asthma and reduced growth of lung function are at increased risk for fixed airflow obstruction and possibly COPD in early adulthood. (Funded by the Parker B. Francis Foundation and others; ClinicalTrials.gov number, NCT00000575.).


Assuntos
Anti-Inflamatórios/uso terapêutico , Asma/fisiopatologia , Pulmão/fisiologia , Administração por Inalação , Adolescente , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Budesonida/uso terapêutico , Criança , Pré-Escolar , Feminino , Volume Expiratório Forçado , Humanos , Estimativa de Kaplan-Meier , Estudos Longitudinais , Pulmão/crescimento & desenvolvimento , Masculino , Nedocromil/uso terapêutico , Fatores de Risco , Fatores Sexuais , Espirometria , Adulto Jovem
2.
Clin Exp Immunol ; 193(2): 207-220, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29645082

RESUMO

Paediatric asthma exacerbations are often caused by rhinovirus (RV). Moreover, 25(OH)-vitamin D3 (VitD3) deficiency during infancy was found associated with asthma. Here, we investigated the innate immune responses to RV and their possible modulation by 25(OH)-VitD3 serum levels in a preschool cohort of children with and without asthma. The innate lymphoid cell type 2 (ILC2)-associated marker, ST2, was found up-regulated in the blood cells of asthmatic children with low serum levels of 25(OH)-VitD3 in the absence of RV in their airways. Furthermore, in blood cells from control and asthmatic children with RV in their airways, soluble (s) ST2 (sST2) protein was found reduced. Asthmatic children with low 25(OH)-VitD3 in serum and with RV in vivo in their airways at the time of the analysis had the lowest sST2 protein levels in the peripheral blood compared to control children without RV and high levels of 25(OH)-VitD3. Amphiregulin (AREG), another ILC2-associated marker, was found induced in the control children with RV in their airways and low serum levels of 25(OH)-VitD3. In conclusion, the anti-inflammatory soluble form of ST2, also known as sST2, in serum correlated directly with interleukin (IL)-33 in the airways of asthmatic children. Furthermore, RV colonization in the airways and low serum levels of 25(OH)-VitD3 were found to be associated with down-regulation of sST2 in serum in paediatric asthma. These data indicate a counter-regulatory role of 25(OH)-VitD3 on RV-induced down-regulation of serum sST2 in paediatric asthma, which is relevant for the therapy of this disease.


Assuntos
Asma/imunologia , Colecalciferol/sangue , Resfriado Comum/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Leucócitos Mononucleares/fisiologia , Sistema Respiratório/metabolismo , Rhinovirus/imunologia , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Imunidade Inata , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/metabolismo , Leucócitos Mononucleares/virologia , Masculino , Regulação para Cima
3.
Clin Exp Allergy ; 48(10): 1297-1304, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29808611

RESUMO

BACKGROUND: Identifying metabolomic profiles of children with asthma has the potential to increase understanding of asthma pathophysiology. OBJECTIVE: To identify differences in plasma metabolites between children with and without current asthma at mid-childhood. METHODS: We used untargeted mass spectrometry to measure plasma metabolites in 237 children (46 current asthma cases and 191 controls) in Project Viva, a birth cohort from eastern Massachusetts, USA. Current asthma was assessed at mid-childhood (mean age 8.0 years). The ability of a broad spectrum metabolic profile to distinguish between cases and controls was assessed using partial least squares discriminant analysis. We used logistic regression models to identify individual metabolites that were differentially abundant by case-control status. We tested significant metabolites for replication in 411 children from the VDAART clinical trial. RESULTS: There was no evidence of a systematic difference in the metabolome of children reporting current asthma vs. healthy controls according to partial least squares discriminant analysis. However, several metabolites were associated with odds of current asthma at a nominally significant threshold (P < .05), including a metabolite of nicotinamide (N1-Methyl-2-pyridone-5-carboxamide (Odds Ratio (OR) = 2.8 (95% CI 1.1-8.0)), a pyrimidine metabolite (5,6-dihydrothymine (OR = 0.4 (95% CI 0.2-0.9)), bile constituents (biliverdin (OR = 0.4 (95%CI 0.1-0.9), taurocholate (OR = 2.0 (95% CI 1.2-3.4)), two peptides likely derived from fibrinopeptide A (ORs from 1.6 to 1.7), and a gut microbiome metabolite (p-cresol sulphate OR = 0.5 (95% CI 0.2-0.9)). The associations for N1-Methyl-2-pyridone-5-carboxamide and p-cresol sulphate replicated in the independent VDAART population (one-sided P values = .03-.04). CONCLUSIONS AND CLINICAL RELEVANCE: Current asthma is nominally associated with altered levels of several metabolites, including metabolites in the nicotinamide pathway, and a bacterial metabolite derived from the gut microbiome.


Assuntos
Asma/sangue , Biomarcadores/sangue , Metaboloma , Metabolômica , Asma/diagnóstico , Asma/imunologia , Estudos de Casos e Controles , Criança , Cromatografia Líquida , Feminino , Humanos , Masculino , Espectrometria de Massas , Metabolômica/métodos , Razão de Chances
4.
Pharmacogenomics J ; 17(2): 137-145, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-26856248

RESUMO

Variation in the expression level and activity of genes involved in drug disposition and action ('pharmacogenes') can affect drug response and toxicity, especially when in tissues of pharmacological importance. Previous studies have relied primarily on microarrays to understand gene expression differences, or have focused on a single tissue or small number of samples. The goal of this study was to use RNA-sequencing (RNA-seq) to determine the expression levels and alternative splicing of 389 Pharmacogenomics Research Network pharmacogenes across four tissues (liver, kidney, heart and adipose) and lymphoblastoid cell lines, which are used widely in pharmacogenomics studies. Analysis of RNA-seq data from 139 different individuals across the 5 tissues (20-45 individuals per tissue type) revealed substantial variation in both expression levels and splicing across samples and tissue types. Comparison with GTEx data yielded a consistent picture. This in-depth exploration also revealed 183 splicing events in pharmacogenes that were previously not annotated. Overall, this study serves as a rich resource for the research community to inform biomarker and drug discovery and use.


Assuntos
Processamento Alternativo , Biologia Computacional , Sequenciamento de Nucleotídeos em Larga Escala , Farmacogenética , Variantes Farmacogenômicos , Análise de Sequência de RNA , Transcriptoma , Tecido Adiposo/metabolismo , Linhagem Celular , Bases de Dados Genéticas , Genótipo , Humanos , Rim/metabolismo , Fígado/metabolismo , Miocárdio/metabolismo , Fenótipo
5.
Allergy ; 72(5): 792-801, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27709636

RESUMO

BACKGROUND: The severity of bronchial hyperresponsiveness (BHR) is a fundamental feature of asthma. The severity of BHR varies between asthmatics and is associated with lack of asthma control. The mechanisms underlying this trait are still unclear. This study aimed to identify genes associated with BHR severity, using a genomewide association study (GWAS) on the slope of BHR in adult asthmatics. METHODS: We performed a GWAS on BHR severity in adult asthmatics from the Dutch Asthma GWAS cohort (n = 650), adjusting for smoking and inhaled corticosteroid use, and verified results in three other cohorts. Furthermore, we performed eQTL and co-expression analyses in lung tissue. RESULTS: In the discovery cohort, one genomewide significant hit located in phosphodiesterase 4D, cAMP-specif (PDE4D) and 26 SNPs with P-values < 1*10-5 were found. None of our findings replicated in adult and childhood replication cohorts jointly. In adult cohorts separately, rs1344110 in pituitary tumour-transforming 1 interacting protein (PTTG1IP) and rs345983 in Mastermind-like 3 (MAML3) replicated nominally; minor alleles of rs345983 and rs1344110 were associated with less severe BHR and higher lung tissue gene expression. PTTG1IP showed significant co-expression with pituitary tumour-transforming 1, the binding factor of PTTG1lP, and with vimentin and E-cadherin1. MAML3 co-expressed significantly with Mastermind-like 2 (MAML2), both involved in Notch signalling. CONCLUSIONS: PTTG1IP and MAML3 are associated with BHR severity in adult asthma. The relevance of these genes is supported by the eQTL analyses and co-expression of PTTG1lP with vimentin and E-cadherin1, and MAML3 with MAML2.


Assuntos
Asma/genética , Hiper-Reatividade Brônquica/genética , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Membrana/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adulto , Asma/diagnóstico , Hiper-Reatividade Brônquica/diagnóstico , Estudos de Coortes , Feminino , Expressão Gênica , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Testes de Função Respiratória , Índice de Gravidade de Doença , Transativadores
6.
Pharmacogenomics J ; 15(3): 272-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25266681

RESUMO

Several reports have shown that statin treatment benefits patients with asthma; however, inconsistent effects have been observed. The mir-152 family (148a, 148b and 152) has been implicated in asthma. These microRNAs suppress HLA-G expression, and rs1063320, a common SNP in the HLA-G 3'UTR that is associated with asthma risk, modulates miRNA binding. We report that statins upregulate mir-148b and 152, and affect HLA-G expression in an rs1063320-dependent fashion. In addition, we found that individuals who carried the G minor allele of rs1063320 had reduced asthma-related exacerbations (emergency department visits, hospitalizations or oral steroid use) compared with non-carriers (P=0.03) in statin users ascertained in the Personalized Medicine Research Project at the Marshfield Clinic (n=421). These findings support the hypothesis that rs1063320 modifies the effect of statin benefit in asthma, and thus may contribute to variation in statin efficacy for the management of this disease.


Assuntos
Asma/tratamento farmacológico , Asma/genética , Antígenos HLA-G/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Regiões 3' não Traduzidas/genética , Alelos , Linhagem Celular Tumoral , Feminino , Células Hep G2 , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Risco
7.
Clin Exp Allergy ; 45(1): 114-25, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25307157

RESUMO

Vitamin D has known effects on lung development and the immune system that may be important in the development, severity, and course of allergic diseases (asthma, eczema, and food allergy). Vitamin D deficiency is prevalent worldwide and may partly explain the increases in asthma and allergic diseases that have occurred over the last 50-60 years. In this review, we explore past and current knowledge on the effect of vitamin D on lung development and immunomodulation and present the evidence of its role in allergic conditions. While there is growing observational and experimental evidence for the role of vitamin D, well-designed and well-powered clinical trials are needed to determine whether supplementation of vitamin D should be recommended in these disorders.


Assuntos
Hipersensibilidade/imunologia , Imunomodulação , Vitamina D/imunologia , Humanos , Hipersensibilidade/epidemiologia , Hipersensibilidade/etiologia , Prevalência , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/imunologia
8.
Pharmacogenomics J ; 14(1): 41-7, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23508266

RESUMO

Reversibility of airway obstruction in response to ß2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534 290 single-nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215 and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (P=1.98 × 10(-7)) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (P=8.51 × 10(-6)). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adolescente , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/genética , Broncodilatadores/administração & dosagem , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
9.
Clin Exp Allergy ; 44(2): 231-7, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24447085

RESUMO

BACKGROUND: Between 75 000 and 125 000 U.S. infants are hospitalized for respiratory syncytial virus (RSV) bronchiolitis every year. Up to half will be diagnosed with asthma in later childhood. Vitamin D deficiency has been associated with susceptibility to asthma and respiratory infections. Measured vitamin D is largely bound to vitamin D-binding protein (VDBP); VDBP levels are influenced by its gene (GC) haplotype. OBJECTIVE: We assessed the relationship between polymorphisms rs7041 and rs4588, which define haplotypes GC1s, GC1f, and GC2, and RSV bronchiolitis susceptibility and subsequent asthma. METHODS: We retrospectively recruited 198 otherwise healthy children (93% White) hospitalized for severe RSV bronchiolitis in Boston and 333 parents into a follow-up study to assess asthma diagnosis. Data were analysed using family-based genetic association tests. We independently validated our results in 465 White children hospitalized with RSV bronchiolitis and 930 White population controls from the Netherlands. RESULTS: The rs7041_C allele (denoting haplotype GC1s) was overtransmitted (P = 0.02, additive model) in the entire Boston cohort, in Whites (P = 0.03), and especially in children subsequently diagnosed with asthma (P = 0.006). The GC1f haplotype was undertransmitted in the asthma subgroups (all races and White, both P < 0.05). The rs7041_C allele was also more frequent in the RSV bronchiolitis group compared with controls (OR 1.12, 95% CI 1.02, 1.4, P = 0.03) in the Netherlands, especially in mechanically ventilated patients (P = 0.009). CONCLUSION AND CLINICAL RELEVANCE: GC1s haplotype carriage may increase the risk of RSV bronchiolitis in infancy and subsequent asthma development. The GC1s haplotype is associated with higher VDBP levels, resulting in less freely available vitamin D. KEY MESSAGES: Vitamin D-binding protein (VDBP) haplotypes influence free vitamin D levels. We report an association between a VDBP haplotype and hospitalization for RSV bronchiolitis in infancy in two independent cohorts.


Assuntos
Bronquiolite Viral/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Infecções por Vírus Respiratório Sincicial/genética , Vírus Sincicial Respiratório Humano , Proteína de Ligação a Vitamina D/genética , Bronquiolite Viral/sangue , Bronquiolite Viral/epidemiologia , Bronquiolite Viral/terapia , Pré-Escolar , Feminino , Seguimentos , Hospitalização , Humanos , Lactente , Masculino , Infecções por Vírus Respiratório Sincicial/sangue , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/terapia , Estudos Retrospectivos , Vitamina D/sangue , Proteína de Ligação a Vitamina D/sangue
10.
Pharmacogenomics J ; 13(3): 242-50, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22370858

RESUMO

The interpatient variability in response to asthma controllers is significant and associates with pharmacogenomic variability. The goal of the present study was to identify novel variants that associate with response to common asthma controllers: fluticasone, combination of fluticasone + salmeterol and montelukast with single nucleotide polymorphisms (SNPs) in ß2-adrenergic receptor, corticosteroid and leukotriene pathway candidate genes. Participants in a large clinical trial of step-down strategies volunteered for this pharmacogenetic study. A total of 169 SNPs in 26 candidate genes were genotyped in 189 Caucasian participants with asthma who took either fluticasone (100 µg bid), fluticasone propionate (100 µg) + salmeterol (50 µg) (FP/Salm) or montelukast (5 or 10 mg) each night for 16 weeks. Primary outcomes were the slopes of plots of Asthma Control Questionnaire (ACQ) scores versus time following randomization; and the percent change in percent predicted FEV1 (ΔFEV1%pred) from enrollment to the end of the study. Associations between SNPs and outcomes were analyzed using general linear models. False discovery rate and Bonferroni corrections were used to correct for multiple comparisons. In all, 16 SNPs in seven genes were significantly associated with outcomes. For FP/Salm, three SNPs in CHRM2 associated with ACQ slope (P=2.8 × 10⁻5), and rs1461496 in HSPA8 associated with ΔFEV1%pred. For fluticasone, five SNPs in CRHR1 (P=1.9 × 10⁻4), and three SNPs in COL2A1 associated with ACQ slope and ΔFEV1%pred, respectively. For montelukast, four SNPs in CHRM2 associated with ΔFEV1%pred and predicted an opposite effect compared with fluticasone (P=9 × 10⁻³). The present study indentified several novel SNPs that associate with response to common asthma controllers, and support further pharmacogenomic study and the use of genetic variants to personalize asthma treatment.


Assuntos
Asma/tratamento farmacológico , Asma/genética , Estudos de Associação Genética , Receptores Adrenérgicos beta 2/genética , Acetatos/administração & dosagem , Administração por Inalação , Adolescente , Albuterol/administração & dosagem , Albuterol/análogos & derivados , Androstadienos/administração & dosagem , Antiasmáticos/administração & dosagem , Asma/patologia , Ensaios Clínicos como Assunto , Ciclopropanos , Combinação de Medicamentos , Feminino , Fluticasona , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medicina de Precisão , Quinolinas/administração & dosagem , Xinafoato de Salmeterol , Sulfetos
11.
Clin Exp Allergy ; 42(2): 229-37, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22010907

RESUMO

BACKGROUND: Distinct receptors likely exist for leukotriene (LT)E(4), a potent mediator of airway inflammation. Purinergic receptor P2Y12 is needed for LTE(4)-induced airways inflammation, and P2Y12 antagonism attenuates house dust mite-induced pulmonary eosinophilia in mice. Although experimental data support a role for P2Y12 in airway inflammation, its role in human asthma has never been studied. OBJECTIVE: To test for association between variants in the P2Y12 gene (P2RY12) and lung function in human subjects with asthma, and to examine for gene-by-environment interaction with house dust mite exposure. METHODS: Nineteen single nucleotide polymorphisms (SNPs) in P2RY12 were genotyped in 422 children with asthma and their parents (n = 1266). Using family based methods, we tested for associations between these SNPs and five lung function measures. We performed haplotype association analyses and tested for gene-by-environment interactions using house dust mite exposure. We used the false discovery rate to account for multiple comparisons. RESULTS: Five SNPs in P2RY12 were associated with multiple lung function measures (P-values 0.006­0.025). Haplotypes in P2RY12 were also associated with lung function (P-values 0.0055­0.046). House dust mite exposure modulated associations between P2RY12 and lung function, with minor allele homozygotes exposed to house dust mite demonstrating worse lung function than those unexposed (significant interaction P-values 0.0028­0.040). CONCLUSIONS AND CLINICAL RELEVANCE: The P2RY12 variants were associated with lung function in a large family-based asthma cohort. House dust mite exposure caused significant gene-by-environment effects. Our findings add the first human evidence to experimental data supporting a role for P2Y12 in lung function. P2Y12 could represent a novel target for asthma treatment.


Assuntos
Asma/genética , Interação Gene-Ambiente , Polimorfismo de Nucleotídeo Único , Pyroglyphidae , Receptores Purinérgicos P2Y12/genética , Animais , Asma/imunologia , Asma/fisiopatologia , Criança , Estudos de Coortes , Feminino , Humanos , Leucotrieno E4/imunologia , Pulmão/imunologia , Pulmão/fisiopatologia , Masculino , Camundongos , Eosinofilia Pulmonar/genética , Eosinofilia Pulmonar/imunologia , Eosinofilia Pulmonar/fisiopatologia , Receptores Purinérgicos P2Y12/imunologia , Testes de Função Respiratória
12.
Clin Exp Allergy ; 42(6): 901-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22909161

RESUMO

BACKGROUND: Increasing evidence links altered intestinal flora in infancy to eczema and asthma. No studies have investigated the influence of maternal intestinal flora on wheezing and eczema in early childhood. OBJECTIVE: To investigate the link between maternal intestinal flora during pregnancy and development of wheeze and eczema in infancy. METHODS: A total of 60 pregnant women from the Boston area gave stool samples during the third trimester of their pregnancy and answered questions during pregnancy about their own health, and about their children's health when the child was 2 and 6 months of age. Quantitative culture was performed on stool samples and measured in log(10)colony-forming units (CFU)/gram stool. Primary outcomes included infant wheeze and eczema in the first 6 months of life. Atopic wheeze, defined as wheeze and eczema, was analysed as a secondary outcome. RESULTS: In multivariate models adjusted for breastfeeding, day care attendance and maternal atopy, higher counts of maternal total aerobes (TA) and enterococci (E) were associated with increased risk of infant wheeze (TA: OR 2.32 for 1 log increase in CFU/g stool [95% CI 1.22, 4.42]; E: OR 1.57 [95% CI 1.06, 2.31]). No organisms were associated with either eczema or atopic wheeze. CONCLUSIONS AND CLINICAL RELEVANCE: In our cohort, higher maternal total aerobes and enterococci were related to increased risk of infant wheeze. Maternal intestinal flora may be an important environmental exposure in early immune system development.


Assuntos
Exposição Ambiental/efeitos adversos , Mucosa Intestinal/microbiologia , Sons Respiratórios/etiologia , Adulto , Aleitamento Materno , Eczema/etiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Fatores de Risco
13.
Clin Exp Allergy ; 42(12): 1724-33, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23181788

RESUMO

BACKGROUND: Asthma is a common chronic respiratory disease in children and adults. An important genetic component to asthma susceptibility has long been recognized, most recently through the identification of several genes (e.g., ORMDL3, PDE4D, HLA-DQ, and TLE4) via genome-wide association studies. OBJECTIVE: To identify genetic variants associated with asthma affection status using genome-wide association data. METHODS: We describe results from a genome-wide association study on asthma performed in 3855 subjects using a panel of 455 089 single nucleotide polymorphisms (SNPs). RESULT: The genome-wide association study resulted in the prioritization of 33 variants for immediate follow-up in a multi-staged replication effort. Of these, a common polymorphism (rs9272346) localizing to within 1 Kb of HLA-DQA1 (chromosome 6p21.3) was associated with asthma in adults (P-value = 2.2E-08) with consistent evidence in the more heterogeneous group of adults and children (P-value = 1.0E-04). Moreover, some genes identified in prior asthma GWAS were nominally associated with asthma in our populations. CONCLUSION: Overall, our findings further replicate the HLA-DQ region in the pathogenesis of asthma. HLA-DQA1 is the fourth member of the HLA family found to be associated with asthma, in addition to the previously identified HLA-DRA, HLA-DQB1 and HLA-DQA2.


Assuntos
Asma/genética , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Cadeias alfa de HLA-DQ/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Asma/epidemiologia , Asma/fisiopatologia , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Pharmacogenomics J ; 11(6): 383-92, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21987090

RESUMO

Despite the availability of several classes of asthma medications and their overall effectiveness, a significant portion of patients fail to respond to these therapeutic agents. Evidence suggests that genetic factors may partly mediate the heterogeneity in asthma treatment response. This review discusses important findings in asthma pharmacogenetic and pharmacogenomic studies conducted to date, examines limitations of these studies and, finally, proposes future research directions in this field. The focus will be on the three major classes of asthma medications: ß-adrenergic receptor agonists, inhaled corticosteroids and leukotriene modifiers. Although many studies are limited by small sample sizes and replication of the findings is needed, several candidate genes have been identified. High-throughput technologies are also allowing for large-scale genetic investigations. Thus, the future is promising for a personalized treatment of asthma, which will improve therapeutic outcomes, minimize side effects and lead to a more cost-effective care.


Assuntos
Asma/terapia , Farmacogenética , Administração Oral , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Agonistas Adrenérgicos beta/uso terapêutico , Asma/genética , Humanos , Antagonistas de Leucotrienos/uso terapêutico
15.
Allergy ; 65(12): 1566-75, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20560908

RESUMO

BACKGROUND: Single nucleotide polymorphisms (SNPs) in thymic stromal lymphopoietin (TSLP) have been associated with IgE (in girls) and asthma (in general). We sought to determine whether TSLP SNPs are associated with asthma in a sex-specific fashion. METHODS: We conducted regular and sex-stratified analyses of association between SNPs in TSLP and asthma in families of children with asthma in Costa Rica. Significant findings were replicated in whites and African-American participants in the Childhood Asthma Management Program, in African-Americans in the Genomic Research on Asthma in the African Diaspora study, in whites and Hispanics in the Children's Health Study, and in whites in the Framingham Heart Study (FHS). MAIN RESULTS: Two SNPs in TSLP (rs1837253 and rs2289276) were significantly associated with a reduced risk of asthma in combined analyses of all cohorts (P values of 2 × 10(-5) and 1 × 10(-5) , respectively). In a sex-stratified analysis, the T allele of rs1837253 was significantly associated with a reduced risk of asthma in males only (P = 3 × 10(-6) ). Alternately, the T allele of rs2289276 was significantly associated with a reduced risk of asthma in females only (P = 2 × 10(-4) ). Findings for rs2289276 were consistent in all cohorts except the FHS. CONCLUSIONS: TSLP variants are associated with asthma in a sex-specific fashion.


Assuntos
Asma/genética , Citocinas/genética , Predisposição Genética para Doença/genética , Caracteres Sexuais , População Negra/genética , Criança , Estudos de Coortes , Costa Rica , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Hispânico ou Latino/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População Branca/genética , Linfopoietina do Estroma do Timo
16.
Am J Physiol Lung Cell Mol Physiol ; 297(3): L496-505, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19574420

RESUMO

Although alveolar wall thinning has been attributed to apoptosis of interstitial lung lipofibroblasts (LFs), the underlying molecular mechanism(s) remains unknown. Although the physiological vitamin D steroid hormone 1alpha,25(OH)(2)D(3) (1,25D) has been suggested as a local paracrine/autocrine effector of fetal lung maturation and is known to affect fibroblast apoptosis, its effects on LF apoptosis are unknown. We determined the role of 1,25D and its metabolite, C-3-epimer (3-epi-1,25D), on LF and alveolar type II (ATII) cell differentiation, proliferation, and apoptosis. Embryonic day 19 Sprague-Dawley fetal rat lung LFs and ATII cells were treated with 1,25D or 3-epi-1,25D (1 x 10(-10) to 1 x 10(-8) M) for 24 h, and cell proliferation, apoptosis, and differentiation were assessed. Both 1,25D and 3-epi-1,25D exhibited dose-dependent increases in expression of the key homeostatic epithelial-mesenchymal differentiation markers, increased LF and ATII cell proliferation, and decreased apoptosis. Furthermore, rat pups administered 1,25D from postnatal days 0 to 14 showed increased expressions of key LF and ATII cell differentiation markers, increased Bcl-2-to-Bax ratio as an index of decreased spontaneous alveolar LF and ATII cell apoptosis, increased alveolar count, and a paradoxical increase in septal thickness. We conclude that spatial- and temporal-specific actions of vitamin D play a critical role in perinatal lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and by modulating LF proliferation/apoptosis. These data not only provide the biological rationale for the presence of an alveolar vitamin D paracrine system, but also provide the first integrated molecular mechanism for increased surfactant synthesis and alveolar septal thinning during perinatal lung maturation.


Assuntos
Apoptose/efeitos dos fármacos , Calcitriol/farmacologia , Comunicação Celular/efeitos dos fármacos , Células Epiteliais/citologia , Fibroblastos/citologia , Mesoderma/citologia , Alvéolos Pulmonares/citologia , Animais , Biomarcadores/metabolismo , Calcitriol/administração & dosagem , Calcitriol/química , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Mesoderma/efeitos dos fármacos , Modelos Biológicos , Comunicação Parácrina/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo
17.
Eur Respir J ; 33(6): 1287-94, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19196819

RESUMO

Vascular endothelial growth factor (VEGF) is an angiogenic factor implicated in asthma severity. The objective of the present study was to determine whether VEGF single nucleotide polymorphisms (SNPs) are associated with asthma, lung function and airway responsiveness. The present authors analysed 10 SNPs in 458 white families in the Childhood Asthma Management Program (CAMP). Tests of association with asthma, lung function and airway responsiveness were performed using PBAT software (Golden Helix, Inc. Bozeman, MT, USA; available at www.goldenhelix.com). Family and population-based, revpeated measures analysis of airflow obstruction were conducted. Replication studies were performed in 412 asthmatic children and their parents from Costa Rica. Associations with asthma, lung function and airway responsiveness were observed in both cohorts. SNP rs833058 was associated with asthma in both cohorts. This SNP was also associated with increased airway responsiveness in both populations. An association of rs4711750 and its haplotype with forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) ratio in both cohorts was observed. Longitudinal analysis in CAMP confirmed an association of rs4711750 with FEV(1)/FVC decline over approximately 4.5 yrs of observation. VEGF polymorphisms are associated with childhood asthma, lung function and airway responsiveness in two populations, suggesting that VEGF polymorphisms influence asthma susceptibility, airflow obstruction and airways responsiveness.


Assuntos
Asma/genética , Asma/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/genética , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Antiasmáticos/administração & dosagem , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Testes de Provocação Brônquica , Criança , Costa Rica , Método Duplo-Cego , Feminino , Volume Expiratório Forçado , Genótipo , Haplótipos , Humanos , Masculino , Nedocromil/administração & dosagem , Nedocromil/uso terapêutico , Fenótipo , Placebos , Polimorfismo de Nucleotídeo Único , Análise de Regressão , Testes de Função Respiratória , Software , Capacidade Vital , População Branca/genética
18.
Clin Pharmacol Ther ; 81(3): 328-45, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17339863

RESUMO

The NIH Pharmacogenetics Research Network (PGRN) is a collaborative group of investigators with a wide range of research interests, but all attempting to correlate drug response with genetic variation. Several research groups concentrate on drugs used to treat specific medical disorders (asthma, depression, cardiovascular disease, addiction of nicotine, and cancer), whereas others are focused on specific groups of proteins that interact with drugs (membrane transporters and phase II drug-metabolizing enzymes). The diverse scientific information is stored and annotated in a publicly accessible knowledge base, the Pharmacogenetics and Pharmacogenomics Knowledge base (PharmGKB). This report highlights selected achievements and scientific approaches as well as hypotheses about future directions of each of the groups within the PGRN. Seven major topics are included: informatics (PharmGKB), cardiovascular, pulmonary, addiction, cancer, transport, and metabolism.


Assuntos
Tratamento Farmacológico , Farmacogenética , Polimorfismo de Nucleotídeo Único , Animais , Fármacos Cardiovasculares/farmacologia , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/genética , Humanos , Informática , Pneumopatias/tratamento farmacológico , Pneumopatias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Preparações Farmacêuticas/metabolismo , Inibidores da Agregação Plaquetária/uso terapêutico , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/reabilitação
19.
Respir Med ; 101(7): 1477-82, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17336509

RESUMO

BACKGROUND: Asthma patients exhibit an increased rate of loss of lung function. Determinants to such decline are largely unknown and the modifying effect of steroid therapy is disputed. This cross-sectional study aimed to elucidate factors contributing to such decline and the possible modifying effect of steroid treatment. METHODS: We analyzed determinants of lung function and airway hyperresponsiveness (AHR) in a Scandinavian study of 2390 subjects from 550 families. Families were selected for the presence of two or more asthmatic children as part of a genetic study, Scandinavian Asthma Genetic Study (SAGA). RESULTS: The primary analysis studied the association between the lung function and delay of inhaled corticosteroids (ICS) after asthma diagnosis among asthmatic children and young adults with a history of regular ICS treatment (N=919). FEV(1) percent predicted (FEV(1)% pred) was 0.25% lower per year of delay from diagnosis until treatment (p=0.039). This association was significantly greater in allergy skin prick test negative children. There was no significant influence of gender, age at asthma onset, or smoking. In the secondary analysis of the whole population of 2390 asthmatics and non-asthmatics, FEV(1)% pred was inversely related to having asthmatic siblings (-7.9%; p<0.0001), asthma diagnosis (-2.7%; p=0.0007), smoking (-3.5%; p=0.0027), and positive allergy skin prick test (-0.47% per test; p=0.012), while positively related to being of female gender (1.8%; p=0.0029). Risk of AHR was higher by having asthmatic siblings (OR 2.7; p<0.0001), being of female gender (OR 2.0; p<0.0001), and having asthma (OR 2.0; p<0.0001). CONCLUSIONS: These data suggest that lung function is lower in asthmatics with delayed introduction of ICS therapy, smoking, and positive allergy skin prick test. Lung function is lower and AHR higher in female asthmatics and subjects with asthmatic siblings or established asthma.


Assuntos
Asma/fisiopatologia , Hiper-Reatividade Brônquica/fisiopatologia , Adolescente , Adulto , Fatores Etários , Asma/tratamento farmacológico , Asma/genética , Hiper-Reatividade Brônquica/genética , Criança , Estudos Transversais , Esquema de Medicação , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Masculino , Fumar/fisiopatologia
20.
Eur Respir J ; 38(6): 1255-7, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22130761
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